Cell migration is fundamental to a variety of biological processes and can be induced by both integrin receptor-mediated signals (haptotaxis migration) and/or soluble growth factor-mediated signals (chemotaxis migration). Integrin receptor engagement activates focal adhesion kinase (FAK, also pp125FAK), a non-receptor protein-tyrosine kinase localized to cell substratum-extracellular matrix (ECM) contact sites that function as part of a cytoskeletal-associated network of signaling proteins (Schlaepfer, D. D., et al., Prog. Biophys. Mol. Biol., 1999, 71, 435-478). In adherent cells, FAK is often associated with integrins at focal adhesions (Schaller, M. D., et al., Proc. Natl. Acad. Sci. USA, 1992, 89, 5192-5196). Numerous other signaling proteins, including other protein tyrosine kinases are associated with FAK at these regions. Phosphorylation of FAK results in activation of the mitogen-activated protein kinase pathway. In addition, FAK regulates activation of phosphatidylinositol 3'-kinase which may serve to prevent apoptosis. FAK has also been shown to be required for internalization of bacteria mediated by invasin (Alrutz, M. A. and Isberg, R. R., Proc. Natl. Acad. Sci. USA, 1998, 95, 13658-13663).
Normal cells typically require anchorage to the extracellular matrix in order to grow. When these cells are removed from the extracellular matrix, they undergo apoptosis. Transformed cells, on the other hand, can grow under anchorage-independent conditions, providing them a growth advantage and the ability to be removed from their normal cellular environment.
Overexpression of FAK is involved in cancer progression. High levels of FAK correlates with invasiveness and metastatic potential in colon tumors (Weiner, T. M., et al., Lancet, 1993, 342, 1024-1025), breast tumors (Owens, L. V., et al., Cancer Res., 1995, 55, 2752-2755), and oral cancers (Kornberg, L. J., Head Neck, 1998, 20, 634-639).
FAK's role in cell migration has led to the speculation that it may be relevant in other diseases such as embryonic development disfunctions and angiogenic disorders (Kornberg, L. J., Head Neck, 1998, 20, 634-639).
There is a lack of specific inhibitors of FAK. Antisense approaches have been a means by which the function of FAK has been investigated. Lou, J. et al. (J. Orthopaedic Res., 1997, 15, 911-918) used an adenoviral based vector to express antisense FAK RNA to show that FAK is involved in wound healing in tendons. Another antisense FAK expression vector containing 400 bp of complementary sequence was used to study the interaction of type I collagen and .alpha.2.beta.1 integrin (Takeuchi, Y., et al., J. Biol. Chem., 1997, 272, 29309-30 29316).
Antisense oligonucleotides have been used in several studies. Tanaka, S. et al. (J. Cell. Biochem., 1995, 58, 424-435) disclose two antisense phosphorothioate oligonucleotides targeted to the start site of mouse FAK. Xu, L. -H., et al. (Cell Growth Diff., 1996, 7, 413-418) disclose two antisense phosphorothioate oligonucleotides targeted within the coding region of human FAK. They also show that FAK antisense treatment could induce apoptosis in tumor cells. Sonoda, Y., et al. (Biochem. Biophys. Res. Comm., 1997, 241, 769-774) also demonstrated a role for FAK in apoptosis using antisense phosphorothioate oligonucleotides targeted to the start site and within the coding region of human FAK. Shibata, K., et al. (Cancer Res., 1998, 58, 900-903) disclose antisense phosphorothioate oligonucleotides targeted to the start site and coding region of human FAK. Narase, K., et al. (Oncogene, 1998, 17, 455-463) disclose an antisense phosphorothioate oligonucleotide targeted to the start site of human FAK.
There remains a long-felt need for improved compositions and methods for inhibiting FAK gene expression.